The cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine inhibits LPS signaling by competing with endotoxin for CD14 binding.
The cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine inhibits LPS signaling by competing with endotoxin for CD14 binding.
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DOI：
10.1016/j.bcp.2010.06.019
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发表时间：
2010-12-15
影响因子：
5.8
通讯作者：
Peri F
中科院分区：
文献类型：
--
作者：
Piazza M;Calabrese V;Baruffa C;Gioannini T;Weiss J;Peri F
天然免疫中细菌内毒素受体的发现，特别是Toll样受体4（TLR 4）的发现，引起了人们对天然免疫系统治疗性调控的极大兴趣。我们最近开发了合成分子，已被证明可以抑制TLR 4在体外和体内的激活。在这里，我们提出了一种新的分子，阳离子两亲物3，4-双（十四烷氧基）苄胺，与以前开发的TLR 4调节剂严格相关的结构的合成和生物学特性。该化合物能够以剂量依赖性方式抑制HEK细胞中LPS刺激的TLR 4活化。为了表征该化合物的作用机制，我们研究了与结合并穿梭LPS至TLR 4的细胞外组分（即LBP、CD 14和MD-2）的可能相互作用。该化合物抑制LBP/CD 14依赖性LPS转移至MD-2.TLR4，导致（LPS-MD-2-TLR 4）2复合物的形成减少。这种作用是由于抑制了LPS从溶液中的聚集体转移到sCD 14，而对LPS从LPS/CD 14穿梭到MD-2的作用很小或没有作用。该化合物还抑制LPS单体从全长CD 14转移至截短的多组氨酸标记的CD 14。综上所述，我们的研究结果强烈表明，该化合物通过竞争性占据CD 14抑制LPS刺激的TLR 4活化，从而减少活化内毒素向MD-2.TLR4的递送。
The identification of the bacterial endotoxin receptors for innate immunity, most notably the Toll-like receptor 4 (TLR4), has sparked great interest in therapeutic manipulation of innate immune system. We have recently developed synthetic molecules that have been shown to inhibit TLR4 activation in vitro and in vivo. Here we present the synthesis and the biological characterization of a new molecule, the cationic amphiphile 3,4-bis(tetradecyloxy)benzylamine, with a structure strictly related to the previously developed TLR4 modulators. This compound is able to inhibit in a dose-dependent manner the LPS-stimulated TLR4 activation in HEK cells. In order to characterize the mechanism of action of this compound, we investigated possible interactions with the extracellular components that bind and shuttle LPS to TLR4, namely LBP, CD14, and MD-2. This compound inhibited LBP/CD14-dependent LPS transfer to MD-2.TLR4, resulting in reduced formation of a (LPS-MD-2-TLR4)2 complex. This effect was due to inhibition of the transfer of LPS from aggregates in solution to sCD14 with little or no effect on LPS shuttling from LPS/CD14 to MD-2. This compound also inhibited transfer of LPS monomer from full length CD14 to a truncated, polyhistidine tagged CD14. Taken together, our findings strongly suggest that this compounds inhibits LPS-stimulated TLR4 activation by competitively occupying CD14 and thereby reducing the delivery of activating endotoxin to MD-2.TLR4.
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6.2
作者：
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